1Department of Physiology and Pharmacology, State University of New York Downstate Medical Center,
Brooklyn, New York, USA2Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York,
USA3Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center,
Brooklyn, New York, USA4The School of Graduate Studies in Molecular and Cellular Science, State University of New York Downstate
Medical Center, Brooklyn, New York, USA5Bio-Defense Systems, Inc, Rockville Center, New York, USA6Orient Biomedica, Estero, Florida, USA7Instituto Bien Salud, Lima, Peru

Magnesium (Mg) is a co-factor for more than 500 enzymes, and is the second most abundant intracellular cation after potassium. It is vital in
numerous physiological, cellular and biochemical functions and systems necessary for life. Approximately 35 years ago, our laboratory suggested
that a progressive, dietary deficiency and/or metabolic induced loss of Mg from the body, beginning early in life, particularly during development
of the coronary arteries, could lead to coronary arterial vasospasm, ischemic heart disease, and sudden-cardiac death (SCD). Herein, we review
evidence for a brand-new, novel hypothesis which combines knowledge suggesting a combined role for hypomagnesemia and platelet-activating
factor (PAF) which may provide insights into unexplained SCD in infants, children, and young adults. This review documents what takes place in
the cardiovascular system when the body and its tissues are subjected to lower than normal dietary Mg intake, and also provides new evidence
for a series of heretofore unknown actions of PAF that are most likely involved and/or trigger coronary arterial vasospasm in the presence of low
concentrations of ionized Mg levels. The roles of vascular remodeling, NF-κB and proto-oncogenes are considered to play major roles in this
hypothesis.

Approximately 35 years ago our laboratory suggested that a progressive,
dietary deficiency and/or a metabolic-induced loss of magnesium (Mg)
from the body beginning early in life, particularly during development of
the coronary arteries, could lead to coronary arterial vasospasm, ischemic
heart disease, and sudden cardiac death (SCD) [1,2]. Ever since this work
was published, a number of clinical studies have been done and published
which support this hypothesis, at least in adults [3-10]. However, little or
no studies have been published to either confirm or deny this hypothesis
in either infants or young children.

Autopsies of children, who have died as a consequence of accidents,
have often demonstrated early signs of atherogenesis (e.g., fatty streaks
on the walls of the aorta and carotid arteries in young children as early
as six years of age) [11]. It should be noted that atherosclerosis is the
number-one cause of premature death in developing countries, including
the United States and plays a major role in etiology of hypertension and
strokes.

Disturbances in diet are known to produce inflammatory lesions,
promote lipid deposition and accelerated growth, and transformation
of the smooth muscle cells in the vascular walls [11-16]. Reduction in
dietary Mg intake has been demonstrated, experimentally, to result in
hypertension [17-20], atherogenesis [15,21-27], and stroke [15,27-34].
Hypermagnesemic diets have been shown to ameliorate hypertension,
atherogenesis, stroke and certain inflammatory responses [34-41]. In
the Western World, dietary intake of Mg is subnormal, with shortfalls of
between 65 and 225 mg of Mg/day, depending upon geographic region
[42,43]. Newly compiled USA NHANES data indicate that approximately
65% of the American population is Mg deficient [44]. Several epidemiologic
studies in North America and Europe have shown that children and adults
consuming Western-type diets are low in Mg content as are pregnant
women (i.e., 30-50% of the RDA for these populations) [42-44].

Using sensitive, specific Mg2+ - ion selective electrodes, it has been
shown that patients with ischemic heart disease, essential hypertension,
renal-diseased induced hypertension, and strokes exhibit significant
depletion of serum and cellular ionized Mg2+, the physiologically-active
Mg [14,25,29-32,45-54]. In addition, we have shown that pregnant
women with gestational diabetes, preeclampsia, and difficult labors
also demonstrate depletion of serum as well as cellular levels of ionized
Mg2+ [48,49,52-54]. Such low levels of ionized Mg, when mimicked in
vitro, result in spasms of peripheral, coronary, placental, neonatal, and
cerebral vascular smooth muscle (VSM) cells, rapid cellular influx and
intracellular release of free Ca2+, well as increasing vascular reactivity
to numerous neurogenic and humoral molecules [2-4,14,19,25-31,55-
62]. Dietary deficiency of Mg in rats has been shown to not only cause
hypertension [17,20], but to also cause vascular remodeling (i.e., arteriolar
wall hypertrophy of unknown origin), rarefaction of capillaries (known
itself to result in hypertension) [18], stiffening of arterial walls [20], as well
as release of cytokines and chemokines (involved in inflammatory and
atherogenic responses) [63-65].

Magnesium Deficiency Results in Activation of NF-κB and
Proto-Oncogenes

The nuclear factor-kappa B (NF-κB) and proto-oncogenes (e.g., c-fos,
c-jun) are two major regulators of growth, differentiation, cell migration,
and cell death (e.g., apoptosis) [66-69]. NF-κB is a transcription factor
and a pleiotropic regulator of numerous genes involved in inflammatory
responses, hypertension, and atherogenesis [12,66,67,69]. Both NF-κB
and the proto-oncogenes are thought to be pivotal in numerous vascular
disease processes such as inflammation, atherogenesis, hypertension, and
ischemic heart disease [12,66,67,69]. It is, however, not clear as to what
initiates expression of these molecular and cellular events, particularly
with respect to how Mg deficiency impacts on these vascular events and
how low Mg causes (or predisposes to) hypertension, intense vasospasm,
inflammation, stroke-like events, cardiac failure , and SCD. Experiments
performed in-vitro and in-vivo on cells and living animals have
demonstrated that short-term magnesium deficiency (MgD) results in
formation/activation of NF-κB and the proto-oncogenes in cardiovascular
tissues and VSM cells [14,25,26,64,65,70].

Sudden Cardiac Death is a Growing World-wide Problem

Sudden infant death syndrome (SIDS) has become a significant problem
without an agreed-upon pathological mechanism(s) [71-76]. Explanations
run the gamut from hypoxia, gene mutations, cardiac conduction
abnormalities, inherited channelopathies, unknown infections,
diaphragmatic dysfunctions, central hypoventillation, susceptibility to
ventricular arrhythmias, etc.. Pediatric sudden cardiac arrest likewise
seems, for the most part, to be a growing problem around the world with
little in the way of an acceptable pathogenic mechaism(s) [71-76]. SCD
accounts for approximately 20% of nearly all deaths in Western countries
with multiple possible, but little agreed-upon explanations. SCD in the
young (<35 yrs of age) has a structural/genetic basis in only about 20%
of all cases in the Western World. In most of these SCD cases, there is no
structural/pathological evidence for any heart abnormalities on autopsies
[71-76].

Approximately 35 years ago, our laboratories reported that mammalian
coronary arteries from neonates as well as adults (including those
obtained from humans) demonstrate intense vasospasm as extracellular
Mg2+ ([Mg2+]0
) concentrations are lowered progressively in in-vitro
studies; the lower the reduction in [Mg2+]0
, and the smaller the coronary
arterial vessel, the more intense the coronary arterial vasospasm [2-
4,14,25-31,55-62]. No vasodilator, including Ca2+ channel blockers can
effectively alleviate these intense coronary vasospasms. These contractile
actions of low Mg2+ are potentiated in the presence of neurohumoral and
circulating vasoconstrictor agents, such as angiotensin II, vasopressin,
serotonin, norepinephrine, and a variety of pressor peptides. Coronary
arterial vessels, particularly small ones (<100 µm in diameter) obtained
from neonatal piglets are exquisitely sensitive to low [Mg2+]0
levels. On the
basis of our studies on the neonatal piglet coronaries, we suggested almost
20 years ago, that low [Mg]0
could play an important role in SIDS and
SCD [77]. Collectively, such findings lead us to conclude that low dietary
Mg levels in pregnant women, infants and children must be taken into
consideration as a major underlying mechanism for unexplained SCD in
infants, children and young adults.

Low Serum Ionized Magnesium Levels found in Infants
and Children in the USA

In view of the above evidence and hypothesis, it is of considerable
interest to point out, here, that several studies, including those done in our
laboratories, have been published which indicate that infants and children
in the USA demonstrate a much higher percentage of abnormally lowered
serum total and ionized Mg levels when compared to adults 35-60 years
of age [14,45,48,49,78-81 ]. Moreover, our studies on infants, children
and pregnant women have shown a high percentage of abnormally low
serum ionized Mg levels as well [14,52-54,82-84]. Taken together, we
believe such clinical studies, collectively, provide substantial evidence for
our hypothesis that unexplained SCD in infants and children possibly is
due, in large measure, to abnormally low serum as well as low VSM and
cardiac myocyte Mg2+ levels. With respect to the latter, we have shown,
working with perfused rat hearts, that even short-term MgD results in
reductions in a variety of hemodynamic functions, i.e., cardiac output,
coronary flows, stroke volume, developed pressures, and cellular highenergy
phosphate levels with concomitant Ca2+ overload [85]. In 1996,
we demonstrated on hearts excised from rats given low Mg diets that
Mg depletion impairs carbohydrate metabolism and lipid metabolism
and results in cardiac calcium overload [86]. We showed more than 40
years ago that Mg2+ blocks the entry and intracellular release of Ca2+ from
both VSM and cardiac myocytes [55,57,59,86-88]. This together with the
adverse effects on both cardiac hemodynamics and energy production
(and utilization) would perforce seriously compromise young hearts and
result in SCD.

Is Genesis and Release of Platelet-Activating Factor (PAF)
the Major Downstream Signal for induction of Coronary
Arterial Vasospasm seen in Low Mg Environments?

Approximately 18 years ago, we reported that reduction of extracellular
Mg2+ levels resulted in generation of variety PAF-like lipids, as seen with
proton nuclear magnetic resonance spectroscopy [87]. At that time,
we suggested that one or more of these PAF-like molecules may be an
initiator of low Mg2+-induced arterial vasopasm and atherogenesis
[87]. Over the intervening two decades, we have found that peripheral,
cerebral and coronary arterial vessels, including neonatal coronaries,
undergo contraction in the presence of low concentrations (<10-6 M) of
PAF by acting on specific VSM membrane PAF receptors [88]. Moreover,
the intense arterial vasospasms observed as [Mg2+]0
is lowered can be
dramatically attenuated in the presence of specific PAF- membrane
receptor blocking drugs [88]. In addition, our new findings indicate that
as [Mg2+]0
is lowered, a rapid (within seconds) generation and release
of PAF is observed in the cultured VSM cells, including those obtained
from neonatal piglets [88]. PAF is now thought to be an important,
maybe critical, molecule in etiology of inflammatory conditions and
atherosclerosis [89-91]. We thus believe that our new findings suggest
major roles for MgD and PAF formation (and PAF-like lipids) in the
cardiovascular manifestations of MgD, inflammation, atherogenesis, and
SCD in children.

Approximately 40 years ago, Russell Ross and colleagues [92] advanced
the hypothesis that atherosclerosis is an inflammatory disease brought
about by injury to the endothelial surfaces of blood vessels in the macroand
microcirculations. The hypothesis stated that different forms of injury
(including hypoxia and ischemia) will result in numerous dysfunctions
in the homeostatic properties of the blood vessels and the underlying
vascular smooth muscle cells, e.g., adhesiveness of leukocytes and/or
platelets, formation/release of cytokines/chemokines and growth factors;
all of these entities needed for atherogenesis are produced in MgD states.
We believe low [Mg2+]0
environments act as triggers to induce local
hypoxic and ischemic events within the macro- and microcirculations
to initiate inflammatory-atherosclerotic sites via initial generation and
release of Ca2+ and PAF. These events could be expected to take place in
developing fetuses in-utero and after birth. Since most diets consumed
in the Western World are deficient in Mg by as much as 65% below
the RDAs for adults, infants and the young, such circumstances would
perforce result in inflammatory conditions, vasospams, atherogenesis,
and SCD.

Conclusions

This article reviews the evidence for a brand-new, novel hypothesis
which combines evidence suggesting a combined role for hypomagnesemia
and PAF which may provide insights into unexplained SCD in infants,
children, and young adults. This report not only documents what takes
place in the cardiovascular system when the body and its tissues are
subjected to lower than normal dietary Mg intake, but provides new
evidence for a series of heretofore unknown actions of PAF that are most
likely involved and/or trigger arterial vasospasm in the presence of low
[Mg2+]0
and probably is a major trigger for unexplained SCD.